N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones

ABSTRACT

Compounds of Formula (I): 
                         
are effective in the treatment of a microbial infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.11/152,002, filed 14 Jun. 2005, now U.S. Pat. No. 7,247,648 B2, which isa divisional application of U.S. Ser. No. 10/702,953 filed 6 Nov. 2003(U.S. Pat. No. 6,930,117 B2), which claims (as does this application)the benefit of U.S. Provisional application Ser. No. 60/425,070, filed 9Nov. 2002, all of which are herein incorporated by reference in theirentirety.

FIELD OF INVENTION

The invention is directed certainN-alkyl-4-methyleneamino-3-hydroxy-2-pyridones useful as antimicrobials.

BACKGROUND OF INVENTION

The chemical and medical literature describes compounds that are said tobe antimicrobial, i.e., capable of destroying or suppressing the growthor reproduction of microorganisms, such as bacteria. For example, suchantibacterials and other antimicrobials are described in Antibiotics,Chemotherapeutics, and Antibacterial Agents for Disease Control (M.Grayson, editor, 1982), and E. Gale et al., The Molecular Basis ofAntibiotic Action 2d edition (1981).

The mechanism of action of these antibacterials vary. One notablemechanism is bacterial aminopeptidase (bMAP) inhibitors. bMAP inhibitionis an important therapeutic target in anti-infective focus area becauseit is involved in translation of mature proteins, and is conserved amongknow pathogenic bacteria. Therefore, inhibition of this enzyme wouldlead to broad spectrum antimicrobial agents.

Many attempts to produce improved antimicrobials yield equivocalresults. Indeed, few antimicrobials are produced that are trulyclinically-acceptable in term of their spectrum of antimicrobialactivity, avoidance of microbial resistance, and pharmacology. Thusthere is a continuing need for broad-spectrum antimicrobials, which areeffective against resistant microbes.

SUMMARY OF INVENTION

The invention provides compounds which are potent inhibitors of bMAP andwhich are effective in treating microbial infections. In particular, thepresent invention relates to compounds having a structure according tothe following Formula (I):

Another aspect of the invention is directed to methods of using thecompounds of Formula (I) for treating a microbial infection in a subjectin need thereof.

Another aspect provide for methods of making compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

I. Terms and Definitions

The following is a list of definitions for terms used herein:

“Acyl” or “carbonyl” is a radical formed by removal of the hydroxy froma carboxylic acid (i.e., R—C(═O)—). Preferred acyl groups include (forexample) acetyl, formyl, and propionyl.

“Alkyl” is a saturated hydrocarbon chain having 1 to 15 carbon atoms,preferably 1 to 10, more preferably 1 to 4 carbon atoms. “Alkenyl” is ahydrocarbon chain having at least one (preferably only one)carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2to 10, more preferably 2 to 4 carbon atoms. “Alkynyl” is a hydrocarbonchain having at least one (preferably only one) carbon-carbon triplebond and having 2 to 15 carbon atoms, preferably 2 to 10, morepreferably 2 to 4 carbon atoms. Alkyl, alkenyl, and alkynyl chains(referred to collectively as “hydrocarbon chains”) may be straight orbranched and may be unsubstituted or substituted. Preferred branchedalkyl, alkenyl, and alkynyl chains have one or two branches, preferablyone branch. Preferred chains are alkyl. Alkyl, alkenyl, and alkynylhydrocarbon chains each may be unsubstituted or substituted with from 1to 4 substituents; when substituted, preferred chains are mono-, di-, ortri-substituted. Alkyl, alkenyl, and alkynyl hydrocarbon chains each maybe substituted with halo, hydroxy, aryloxy (e.g., phenoxy),heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl (e.g., phenyl),heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido,acylamino, keto, thioketo, cyano, or any combination thereof. Preferredhydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl,vinyl, allyl, butenyl, and exomethylenyl.

Also, as referred to herein, a “lower” alkyl, alkenyl or alkynyl moiety(e.g., “lower alkyl”) is a chain comprised of 1 to 6, preferably from 1to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4,carbon atoms in the case of alkenyl, and alkynyl.

“Alkoxy” is an oxygen radical having a hydrocarbon chain substituent,where the hydrocarbon chain is an alkyl or alkenyl (i.e., —O-alkyl or—O-alkenyl). Preferred alkoxy groups include (for example) methoxy,ethoxy, propoxy and allyloxy.

“Aryl” is an aromatic hydrocarbon ring. Aryl rings are monocyclic orfused bicyclic ring systems. Monocyclic aryl rings contain 6 carbonatoms in the ring. Monocyclic aryl rings are also referred to as phenylrings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably9 to 12 carbon atoms, in the ring. Bicyclic aryl rings include ringsystems wherein one ring is aryl and the other ring is aryl, cycloalkyl,or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6-or7-membered rings fused to 5-, 6-, or 7-membered rings. Aryl rings may beunsubstituted or substituted with from 1 to 4 substituents on the ring.Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy,amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy,alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy,heteroaryloxy, or any combination thereof. Preferred aryl rings includenaphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radicalis phenyl.

“Aryloxy” is an oxygen radical having an aryl substituent (i.e.,—O-aryl). Preferred aryloxy groups include (for example) phenoxy,napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.

“Cycloalkyl” is a saturated or unsaturated hydrocarbon ring. Cycloalkylrings are not aromatic. Cycloalkyl rings are monocyclic, or are fused,spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl ringscontain from about 3 to about 9 carbon atoms, preferably from 3 to 7carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring.Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6-or 7-memberedrings fused to 5-, 6-, or 7-membered rings. Cycloalkyl rings may beunsubstituted or substituted with from 1 to 4 substituents on the ring.Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl,haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy,heteroaryloxy, or any combination thereof. Preferred cycloalkyl ringsinclude cyclopropyl, cyclopentyl, and cyclohexyl.

“Halo” or “halogen” is fluoro, chloro, bromo or iodo. Preferred halo arefluoro, chloro and bromo; more preferred typically are chloro andfluoro, especially fluoro.

“Haloalkyl” is a straight, branched, or cyclic hydrocarbon substitutedwith one or more halo substituents. Preferred are C₁-C₁₂ haloalkyls;more preferred are C₁-C₆ haloalkyls; still more preferred still areC₁-C₃ haloalkyls. Preferred halo substituents are fluoro and chloro. Themost preferred haloalkyl is trifluoromethyl.

“Heteroatom” is a nitrogen, sulfur, or oxygen atom. Groups containingmore than one heteroatom may contain different heteroatoms.

“Heteroalkyl” is a saturated or unsaturated chain containing carbon andat least one heteroatom, wherein no two heteroatoms are adjacent.Heteroalkyl chains contain from 2 to 15 member atoms (carbon andheteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5.For example, alkoxy (i.e., —O-alkyl or —O-heteroalkyl) radicals areincluded in heteroalkyl. Heteroalkyl chains may be straight or branched.Preferred branched heteroalkyl have one or two branches, preferably onebranch. Preferred heteroalkyl are saturated. Unsaturated heteroalkylhave one or more carbon-carbon double bonds and/or one or morecarbon-carbon triple bonds. Preferred unsaturated heteroalkyls have oneor two double bonds or one triple bond, more preferably one double bond.Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4substituents. Preferred substituted heteroalkyl are mono-, di-, ortri-substituted. Heteroalkyl may be substituted with lower alkyl,haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy,monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle,amino, acylamino, amido, keto, thioketo, cyano, or any combinationthereof.

“Heteroaryl” is an aromatic ring containing carbon atoms and from 1 toabout 6 heteroatoms in the ring. Heteroaryl rings are monocyclic orfused bicyclic ring systems. Monocyclic heteroaryl rings contain fromabout 5 to about 9 member atoms (carbon and heteroatoms), preferably 5or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8to 17 member atoms, preferably 8 to 12 member atoms, in the ring.Bicyclic heteroaryl rings include ring systems wherein one ring isheteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise5-, 6-or 7-membered rings fused to 5-, 6-, or 7-membered rings.Heteroaryl rings may be unsubstituted or substituted with from 1 to 4substituents on the ring. Heteroaryl may be substituted with halo,cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl,haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combinationthereof. Preferred heteroaryl rings include, but are not limited to, thefollowing:

“Heteroaryloxy” is an oxygen radical having a heteroaryl substituent(i.e., —O-heteroaryl). Preferred heteroaryloxy groups include (forexample) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy,(thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, andbenzothiazolyloxy.

“Heteroaryloxy” is a saturated or unsaturated ring containing carbonatoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring.Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings aremonocyclic, or are fused, bridged, or spiro bicyclic ring systems.Monocyclic heterocycloalkyl rings contain from about 3 to about 9 memberatoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, inthe ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 memberatoms, preferably 7 to 12 member atoms, in the ring. Bicyclicheterocycloalkyl rings contain from about 7 to about 17 ring atoms,preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings maybe fused, Spiro, or bridged ring systems. Preferred bicyclicheterocycloalkyl rings comprise 5-, 6-or 7-membered rings fused to 5-,6-, or 7-membered rings. Heterocycloalkyl rings may be unsubstituted orsubstituted with from 1 to 4 substituents on the ring. Heterocycloalkylmay be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo,amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl,alkoxy, aryloxy or any combination thereof. Preferred substituents onheterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkylrings include, but are not limited to, the following:

“Spirocycle” is an alkyl or heteroalkyl diradical substituent of alkylor heteroalkyl wherein said diradical substituent is attached geminallyand wherein said diradical substituent forms a ring, said ringcontaining 4 to 8 member atoms (carbon or heteroatom), preferably 5 or 6member atoms.

While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may besubstituted with hydroxy, amino, and amido groups as stated above, thefollowing are not envisioned in the invention:

-   -   1. Enols (OH attached to a carbon bearing a double bond).    -   2. Amino groups attached to a carbon bearing a double bond        (except for vinylogous amides).    -   3. More than one hydroxy, amino, or amido attached to a single        carbon (except where two Nitrogen atoms are attached to a single        carbon atom and all three atoms are member atoms within a        heterocycloalkyl ring).    -   4. Hydroxy, amino, or amido attached to a carbon that also has a        heteroatom attached to it.    -   5. Hydroxy, amino, or amido attached to a carbon that also has a        halogen attached to it.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., hydroxamic or carboxylic acid) group, or an anionic saltformed at any basic (e.g., amino) group. Many such salts are known inthe art, as described in World Patent Publication 87/05297, Johnston etal., published September 11. Preferred cationic salts include the alkalimetal salts (such as sodium and potassium), and alkaline earth metalsalts (such as magnesium and calcium) and organic salts. Preferredanionic salts include the halides (such as chloride salts), sulfonates,carboxylates, phosphates, and the like.

Such salts are well understood by the skilled artisan, and the skilledartisan is able to prepare any number of salts given the knowledge inthe art. Furthermore, it is recognized that the skilled artisan mayprefer one salt over another for reasons of solubility, stability,formulation ease and the like. Determination and optimization of suchsalts is within the purview of the skilled artisan's practice.

A “biohydrolyzable amide” is an amide compound of the present inventionthat does not interfere with the activity of the compound, or that isreadily converted in vivo by an animal, preferably a mammal, morepreferably a human subject, to yield a pharmaceutically active compound.Examples of such amide derivatives are alkoxyamides, where the hydroxylhydrogen of the hydroxamic acid of a Formula (I) compound is replaced byan alkyl moiety, and acyloxyamides, where the hydroxyl hydrogen isreplaced by an acyl moiety (i.e., R—C(═O)—).

A “biohydrolyzable hydroxy imide” is an imide of a hydroxamicacid-containing compound of the present invention that does notinterfere with the activity of the compound, or that is readilyconverted in vivo by an animal, preferably a mammal, more preferably ahuman subject to yield a pharmaceutically active compound. Examples ofsuch imide derivatives are those where the amino hydrogen of thehydroxamic acid of a Formula (I) compound is replaced by an acyl moiety(i.e., R—C(═O)—).

A “biohydrolyzable ester” is an ester of a carboxylic acid-containingcompound of the present invention that does not interfere with theactivity of the compound or that is readily converted by an animal toyield a pharmaceutically active compound. Such esters include loweralkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl,acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl andpivaloyloxyethyl esters), lactonyl esters (such as phthalidyl andthiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such asmethoxycarbbnyloxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline estersand alkyl acylamino alkyl esters (such as acetamidomethyl esters):

A “solvate” is a complex formed by the combination of a solute (e.g., acompound of formula (I)) and a solvent (e.g., water). See J. Honig etal., The Van Nostrand Chemist's Dictionary, p. 650 (1953).Pharmaceutically-acceptable solvents used according to this inventioninclude those that do not interfere with the biological activity of theinventive compound (e.g., water, ethanol, acetic acid,N,N-dimethylformamide and others known or readily determined by theskilled artisan).

The terms “optical isomer”, “stereoisomer”, and “diastereomer” have thestandard art recognized meanings (see, e.g., Hawley's Condensed ChemicalDictionary, 11th Ed.). The illustrations of specific protected forms andother derivatives of the compounds of the instant invention are notintended to be limiting. The application of other useful protectinggroups, salt forms, etc. is within the ability of the skilled artisan.

II. Compounds

The subject invention involves compounds of Formula (I):

The following provides a description of particularly preferred moieties,but is not intended to limit the scope of the claims.

Each R¹ is independently chosen from hydrogen, halo, cyano, hydroxy,carboxy, keto, thioketo, amino, acylamino, acyl, amido, phenyl, aryloxy,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl. In one embodiment, R ishydrogen.

Each R² is independently chosen from hydrogen, halo, cyano, hydroxy,carboxy, keto, thioketo, amino, acylamino, acyl, amido, phenyl, aryloxy,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl. In one embodiment, R² ishydrogen.

R³ and R⁴ are each independently chosen from hydrogen, alkyl, alkenyl,alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,alkylheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl andalkylheterocycloalkyl; or R³ and R⁴, together with the Nitrogen atom towhich they are bonded, join to form heteroaryl, or heterocycloalkylmoieties, optionally substituted with at least hydrogen, halo, cyano,hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, phenyl,aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, spirocyloalkyl andcombinations thereof.

R⁵ and R⁶ are each independently chosen from of hydrogen, halo, cyano,hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, phenyl,aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl. In one embodiment, R⁵ andR⁶ are each hydrogen.

III. Compound Preparation

The compounds of the invention can be prepared using a variety ofprocedures. Particularly preferred syntheses are described in thefollowing general reaction scheme. (The R groups used to illustrate thereaction schemes do not necessarily correlate to the respective R groupsused to describe the various aspects of the Formula I compounds. Thatis, for example, R¹ in Formula (I) does not represent the same moiety asR¹ here). Specific examples for making the compounds of the presentinvention are set forth in Section VII, below.

In general scheme I, the starting material S1 is known, made by knownmethods, or are commercially available. S1 is protected by beingsubjected to an alkylating agent in the presence of base in an alcoholsolvent to produce compound S2, wherein “Ar” is defined as an arylmoiety. As used herein, “alkylating agent” means an agent that reactswith S1, resulting in both the nitrogen and hydroxyl of S1 forming a newcarbon-nitrogen and carbon-oxygen bond, respectively. Non-limitingexamples of an alkylating agent include halomethylenearyl orhalomethyleneheteroaryl. An example of an alcohol solvent is methanol.Suitable examples of base include potassium hydroxide, potassiumcarbonate, potassium tert-butoxide, sodium methoxide, and Triton B.

In turn, S2 is selectively deprotected by a hydrogenating agent to yieldS3. As used herein, “hydrogenating agent” means addition of hydrogenatom to another atom residue like carbon. Suitable examples of ahydrogenating agent include palladium on carbon or rhodium on carbon, ina methanol solvent and under hydrogen gas.

Lastly, S3 is formylated and aminated by a formylating agent and anaminating agent, respectively. As used herein, “formylating agent” meansan agent that transfers a methylene unit “CH₂” or

Non-limiting examples of a formylating agent are paraformaldehyde,formaldehyde, formic acid-formamide, formylimidazole, p-nitrophenylformate. Alternatively, any aldehyde (R—COH) can be used as formylatingagent in this application. The result is that the methylene unit isfurther branched based upon the aldehyde that is used. These formulatingagents are commercially available or made by known methods. As usedherein, “aminating agent” means any primary of amine of formula NHR³ orsecondary amine of formula NR³R⁴. These amines are commerciallyavailable or made by known methods. For example, many such amines can beidentified using ChemOffice WebServer and the ChemACX databases. Theseamines can be further modified by those methods well-known in the art.

These steps may be varied to increase yield of desired product. Theskilled artisan will recognize the judicious choice of reactants,solvents, and temperatures as an important components in any successfulsynthesis. Determination of optimal conditions, etc. is routine. Thusthe skilled artisan can make a variety of compounds using the guidanceof the schemes above.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction; that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations ofhydroxyls and the like, acylations, aromatic substitutions, bothelectrophilic and nucleophilic, etherifications, esterification andsaponification and the like. Examples of these manipulations arediscussed in standard texts such as March, Advanced Organic Chemistry(Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) andother art that the skilled artisan is aware of.

The skilled artisan will also readily appreciate that certain reactionsare best carried out when another potentially reactive functionality onthe molecule is masked or protected, thus avoiding any undesirable sidereactions and/or increasing the yield of the reaction. Often the skilledartisan utilizes protecting groups to accomplish such increased yieldsor to avoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations can be found for example in T.Greene, Protecting Groups in Organic Synthesis.

The compounds of the invention may have one or more chiral centers. As aresult, one may selectively prepare one optical isomer, includingdiastereomer and enantiomer, over another, for example by chiralstarting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers may beseparated using known methods, such as chiral salts, chiralchromatography and the like.

In addition, it is recognized that one optical isomer, includingdiastereomer and enantiomer, or stereoisomer may have favorableproperties over the other. Thus when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

IV. Methods of Use

The compounds of the present invention are useful as antimicrobials.Without wishing to be bound by theory, these compounds could act aschelators of the cobalt ion of the bMap active site. As chelators, thesecompounds could as act as inhibitors of metalloenzymes.

V. Compositions

The compositions of the invention comprise:

-   -   (a) a safe and effective amount of a compound of the invention;        and    -   (b) a pharmaceutically-acceptable carrier.

The invention compounds can therefore be formulated into pharmaceuticalcompositions for use in treatment microbial infections. Standardpharmaceutical formulation techniques are used, such as those disclosedin Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., latest edition.

A “safe and effective amount” of a Formula (I) compound is an amountthat is effective, to destroy or suppress the growth or reproduction ofmicroorganisms, in an animal, preferably a mammal, more preferably ahuman subject, without undue adverse side effects (such as toxicity,irritation, or allergic response), commensurate with a reasonablebenefit/risk ratio when used in the manner of this invention. Thespecific “safe and effective amount” will, obviously, vary with suchfactors as the particular condition being treated, the physicalcondition of the patient, the duration of treatment, the nature ofconcurrent therapy (if any), the specific dosage form to be used, thecarrier employed, the solubility of the Formula (I) compound therein,and the dosage regimen desired for the composition.

In addition to the subject compound, the compositions of the subjectinvention contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to an animal, preferably a mammal,more preferably a human. The term “compatible”, as used herein, meansthat the components of the composition are capable of being commingledwith the subject compound, and with each other, in a manner such thatthere is no interaction which would substantially reduce thepharmaceutical efficacy of the composition under ordinary usesituations. Pharmaceutically-acceptable carriers must, of course, be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal, preferably a mammal, morepreferably a human being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

The compositions of this invention are preferably provided in unitdosage form. As used herein, a “unit dosage form” is a composition ofthis invention containing an amount of a Formula (I) compound that issuitable for administration to an animal, preferably a mammal, morepreferably a human subject, in a single dose, according to good medicalpractice. These compositions preferably contain from about 5 mg(milligrams) to about 1000 mg, more preferably from about 10 mg to about500 mg, more preferably from about 10 mg to about 300 mg, of a Formula(I) compound.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical, nasal, ocular orparenteral administration. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the inhibitoryactivity of the Formula (I) compound. The amount of carrier employed inconjunction with the Formula (I) compound is sufficient to provide apractical quantity of material for administration per unit dose of theFormula (I) compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references, all incorporated by reference herein: ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms Tablets (1981); and Ansel,Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of the Formula (I) compound. Tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, or multiple-compressed, containing suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Liquid oral dosageforms include aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules, andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring agentsand flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrarits such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of the subjectinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, Avicel™ RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit”coatings, waxes and shellac.

Compositions of the subject invention may optionally include other drugactives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

The compositions of this invention can also be administered topically toa subject, e.g., by the direct laying on or spreading of the compositionon the epidermal or epithelial tissue of the subject, or transdermallyvia a “patch”. Such compositions include, for example, lotions, creams,solutions, gels and solids. These topical compositions preferablycomprise a safe and effective amount, usually at least about 0.1%, andpreferably from about 1% to about 5%, of the Formula (I) compound.Suitable carriers for topical administration preferably remain in placeon the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein the Formula(I) compound. The carrier may include pharmaceutically-acceptableemollients, emulsifiers, thickening agents, solvents and the like.

VI. Methods of Administration

This invention also provides methods of treating a microbial infectionin a human or other animal subject, by administering a safe andeffective amount of a Formula (I) compound to said subject.

Compositions of this invention can be administered topically orsystemically. Systemic application includes any method of introducingFormula (I) compound into the tissues of the body, e.g., transdermal,intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The Formula (I) compounds of the present invention arepreferably administered orally.

The specific dosage of inhibitor to be administered, as well as theduration of treatment, and whether the treatment is topical or systemicare interdependent. The dosage and treatment regimen will also dependupon such factors as the specific Formula (I) compound used, thetreatment indication, the ability of the Formula (I) compound to reachminimum inhibitory concentrations at the site infection, the personalattributes of the subject (such as weight), compliance with thetreatment regimen, and the presence and severity of any side effects ofthe treatment.

Typically, for a human adult (weighing approximately 70 kilograms), fromabout 5 mg to about 3000 mg, more preferably from about 5 mg to about1000 mg, more preferably from about 10 mg to about 100 mg, of Formula(I) compound are administered per day for systemic administration. It isunderstood that these dosage ranges are by way of example only, and thatdaily administration can be adjusted depending on the factors listedabove.

A preferred method of systemic administration is oral. Individual dosesof from about 10 mg to about 1000 mg, preferably from about 10 mg toabout 300 mg are preferred.

Topical administration can be used to deliver the Formula (I) compoundsystemically, or to treat a subject locally. The amounts of Formula (I)compound to be topically administered depends upon such factors as skinsensitivity, type and location of the tissue to be treated, thecomposition and carrier (if any) to be administered, the particularFormula (I) compound to be administered, as well as the particulardisorder to be treated and the extent to which systemic (asdistinguished from local) effects are desired.

For localized conditions, topical administration is preferred. Forexample, to treat an microbial infection of the eye, direct applicationto the affected eye may employ a formulation as eyedrops or aerosol. Forcorneal treatment, the compounds of the invention can also be formulatedas gels, drops or ointments, or can be incorporated into collagen or ahydrophilic polymer shield. The materials can also be inserted as acontact lens or reservoir or as a subconjunctival formulation. Fortreatment of a microbial infection of the skin, the compound is appliedlocally and topically, in a gel, paste, salve or ointment. For treatmentof oral infections, the compound may be applied locally in a gel, paste,mouth wash, or implant. The mode of treatment thus reflects the natureof the condition and suitable formulations for any selected route areavailable in the art.

In all of the foregoing, of course, the compounds of the invention canbe administered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication.

VII. EXAMPLES Compound Preparation

The following substructure and table show the structure of Examples 1-38compounds made according to the procedures described herein below. The Ror X groups used to illustrate the compound examples do not necessarilycorrelate to the respective R and X groups used to describe the variousmoieties of Formula (I) in the claims.

A. Synthesis of Preferred Intermediate N-benzyl-3-hydroxypyridin-2-one

1-Benzyl-3-benzyloxy-1H-pyridin-2-one (Ghosh et al, J. Org. Chem. 1989,54, 5073) is dissolved in anhydrous methanol (10 mL) and to thethoroughly degassed solution is added a catalytic amount of Pd—C (0.1%).The mixture is hydrogenated under a balloon of hydrogen, until all thestarting material is consumed. At the completion, the solution isfiltered through Celite™. The solvent is removed in vacuo, and theresidue is washed with ether, to afford the desired product. ¹H NMR (300MHz, CDCl₃) δ 5.15 (s, 2H), 6.14 (t, J=7.2 Hz, 1H); 6.71 (m, 1H), 7.31(m, 6H), 9.07 (s, 1H).B. General Procedure for the Three Component Coupling Between Pyridones,Formaldehyde and Amines:

Pyridone intermediate of step A (1 eqv.), HCHO or aldehyde (2.2 eqv.)are mixed together in aqueous EtOH (10 mL) and stirred for 30 min. Amine(2.2 eqv.) is added, stirred for 12 h, and concentrated. The residue isdissolved in EtOH (10 mL) and purified via HPLC (water/acetonitrile/0.1%TFA). The product is isolated as the TFA salt unless indicatedotherwise. The yields are 75-95%.

C. Examples 1-38. Examples are prepared in accordance with the abovemethod by varying the amine.

Exam- ple R1 X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

Example 1

1-Benzyl-3-hydroxy-4-(piperidin-1-ylmethyl)-1H-pyridin-2-one ¹H NMR (300MHz, CD₃OD) δ 1.81 (m, 6H), 3.07 (m, 2H), 3.51 (m, 2H), 4.23 (s, 2H),5.24 (s, 2H), 6.31 (d, J=6.9 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR (252 MHz,CD₃OD) δ 85.5; 13C NMR (75 MHz, DMSO) δ 21.3, 22.7, 51.8, 52.5, 53.1,106.4, 117.4, 127.7, 128.0, 128.2, 128.9, 137.3, 147.4, 158.0; ES MS(M+1) 299.12; HRMS Calcd. For C₁₈H₂₂N₂O₂, 298.38. Found (M+1) 299.17.

Example 2

1-Benzyl-3-hydroxy-4-(morpholin-4-ylmethyl)-1H-pyridin-2-one ¹H NMR (300MHz, DMSO) δ 3.25 (m, 4H), 3.81 (m, 4H), 4.18 (s, 2H), 5.17 (s, 2H),6.31 (d, J=6.9 Hz, 1H), 7.35 (m, 6H); ¹⁹FNMR (300 MHz, DMSO) δ 88.5; ¹³CNMR (300 MHz, DMSO) δ 51.6, 51.8, 53.4, 63.5, 107.9, 119.1, 127.8,128.0, 128.2, 128.9, 137.3, 147.5, 158.3; ES MS (M+1) 301.12; HRMSCalcd. For C₁₇H₂₀N₂O₃, 300.35.

Example 3

1-Benzyl-3-hydroxy-4-(thiamorpholin-4-ylmethyl)-1H-pyridin-2-one ¹H NMR(300 MHz, DMSO) δ 2.92 (m, 4H), 3.38 (m, 4H), 4.17 (s, 2H), 5.16 (s,2H), 6.29 (d, J=7.5 Hz, 1H), 7.34 (m, 6H), 9.97 (s, 1H); ¹⁹F NMR (300MHz, DMSO) δ 88.4; ¹³C NMR (75 MHz, DMSO) δ 24.3, 51.9, 53.4, 53.7,107.9, 110.9, 127.8, 128.0, 128.2, 128.8, 137.2, 147.6, 157.6; ES MS(M+1) 317.14; HRMS Calcd. For C₁₇H₂₀N₂O₂S, 316.42. Found: (M+1) 317.13.

Example 4

1-Benzyl-3-hydroxy-4-(thiazolidin-3-ylmethyl)-1H-pyridin-2-one ¹HNMR(300 MHz, DMSO) δ 3.09 (t, J=6.3 Hz, 2H), 3.42 (t, J=6.3 Hz, 2H), 4.03(s, 2H), 4.29 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 10.48 (broad s, 1H); ¹⁹F NMR (300 MHz, DMSO) δ 87.9; ¹³C NMR (75MHz, DMSO) δ 28.3, 48.3, 50.1, 56.3, 57.0, 107.4, 122.1, 127.8, 128.2,128.8, 137.4, 146.3, 157.6; ES MS (M+1) 303.08; Anal. Calcd forC₁₈H₁₉N₂O₄SF, C, 51.92; H, 4.60; N, 6.73; S, 7.70. Found: C, 51.67; H,4.48; N, 6.69; S, 7.65.

Example 5

1-Benzyl-4-(benzylaminomethyl)-3-hydroxy-1H-pyridin-2-one ¹HNMR (300MHz, DMSO) δ 4.01 (s, 2H), 4.20 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2Hz, 1H), 7.36 (m, 11H), 9.16 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ88.6; ¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 321.16; Anal. Calcd. ForC₂₂H₂₁F₃N₂O₄, C, 60.83; H, 4.87; N, 6.45. Found: C, 60.75; H, 4.56; N,6.34.

Example 6

1-Benzyl-3-hydroxy-4-{[2-(pyridin-2-yl)ethylamino]methyl}-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 3.26 (m, 2H), 3.37 (m, 2H), 4.08 (s, 2H), 5.17(s, 2H); 6.34 (d, J=7.2 Hz, 1H), 7.38 (m, 6H), 7.86 (d, J=5.7 Hz, 2H),8.84 (m, 2H), 9.32 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.6; ¹³CNMR (75 MHz, DMSO) δ 31.5, 44.1, 46.3, 51.8, 106.9, 114.8, 127.1, 128.1,128.8, 137.4, 143.8, 146.1, 155.3, 157.5, 158.4; ES MS (M+1) 336.18;HRMS Calcd For C₂₀H₂₁N₃O₂, 335.40. Found: 336.16.

Example 7

1-Benzyl-3-hydroxy-4-(pyrrolidin-1-ylmethyl)-1H-pyridin-2-one ¹H NMR(300 MHz, DMSO) δ 1.96 (s, 4H), 3.16 (s, 2H), 3.43 (s, 2H), 4.23 (s,4H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252MHz, DMSO) δ 88.7; ¹³C NMR (75 MHz, DMSO) δ 22.8, 50.9, 51.8, 53.7,107.3, 118.0, 128.0, 128.2, 128.9, 137.3, 146.7, 157.6; ES MS (M+1)285.13; Anal. Calcd. For C₁₉H₂₁F₃N₂O₄, C, 57.28; H, 5.31; N, 7.03.Found: C, 57.10; H, 5.11, N, 7.02.

Example 8

1-Benzyl-4-(4-benzylpiperidin-1-ylmethyl)-3-hydroxy-1H-pyridin-2-one ¹HNMR (DMSO) δ 1.43 (m, 2H), 1.72 (m, 4H), 2.96 (m, 2H), 3.41 (m, 3H),4.09 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.35 (m, 11H); ¹⁹FNMR (252 MHz, DMSO) 88.8; ¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 389.21;HRMS Calcd. For C₂₅H₂₈N₂O₂, 388.50. Found (M+1) 389.22.

Example 9

1-Benzyl-4-(4-benzylpiperazin-1-ylmethyl)-3-hydroxy-1H-pyrdin-2-one ¹HNMR (300 MHz, DMSO) δ 3.11 (broad s, 4H), 3.81 (s, 2H), 4.18 (s, 2H),5.15 (s, 2H), 6.24 (d, J=7.2 Hz, 1H), 7.34 (m, 6H), 7.46 (m, 5H); ¹⁹FNMR (252 MHz, DMSO) δ 88.2; 13C (75 MHz, DMSO) δ ; ES MS (M+1) 390.21;HRMS Calcd. For C₂₄H₂₇N₃O₂, 389.49. Found (M+1) 390.21.

Example 101-Benzyl-3-Hydroxy-4-(3-hydroxypyrrolidin-1-ylmethyl)-1H-pyrdin-2-one

¹HNMR (300 MHz, DMSO) δ 1.90 (m, 1H), 3.18 (m, 2H), 3.47 (m, 3H), 4.24(s, 2H), 4.43 (s, 1H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H); ¹⁹F NMR (252 MHz, DMSO) δ 89.0; ¹³C NMR (75 MHz, DMSO) δ 51.8,52.6, 61.3, 68.6, 107.4, 117.9, 128.0, 128.2, 128.9, 137.3, 146.7,157.6; ES MS (M+1) 301.13; HRMS Calcd. For C₁₇H₂₀N₂O₃, 300.35. Found:(M+1) 301.15.

Example 11

1-Benzyl-4-[([1,3]dioxolan-2-ylmethylmethylamino)methyl]-3-hydroxy-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 2.81 (s, 3H), 3.35 (d, J=3.9 Hz, 2H), 3.89 (m,2H), 4.01 (m, 2H), 4.21 (m, 2H), 5.17 (s, 2H); 5.27 (t, J=3.9 Hz, 1H),6.34 (d, J=7.2 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5;¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 331.18; HRMS Calcd. ForC₁₈H₂₂N₂O₄, 330.38. Found (M+1) 331.16.

Example 12

1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}-1H-pyrdin-2-one¹H NMR (300 MHz, DMSO) δ 1.56 (m, 1H), 1.86 (m, 2H), 1.99 (m, 1H), 2.92(m, 1H), 3.05 (m, 1H), 3.80 (m, 2H), 4.09 (m, 3H), 5.16 (s, 2H), 6.34(d, J=7.2 Hz, 1H), 7.34 (m, 6H); 8.91 (broad s, 1H); ¹⁹F NMR (252 MHz,DMSO) δ 88.5; ¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 315.16; HRMS. Calcd.For C₁₈H₂₂N₂O₃, 314.38. Found (M+1) 315.16.

Example 13

1-Benzyl-3-hydroxy-4-[(2-methoxyethylamino)methyl]-1H-pyridin-2-one ¹HNMR (300 MHz, DMSO) δ 3.13 (broad s, 2H), 3.30 (s, 3H), 3.59 (t, J=5.4Hz, 2H), 4.02 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 8.91 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.4; ¹³C NMR (252MHz, DMSO) δ; ES MS (M+1) 289.13; HRMS Calcd. For C₁₆H₂₀N₂O₃, 288.34.Found (M+1) 289.15.

Example 141-Benzyl-4-(1,4-dioxa-8-azaspiro[4,5]dec-8-ylmethyl)-3-hydroxy-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 1.90 (m, 4H), 3.11 (m, 2H), 3.43 (m, 2H), 3.93(s, 4H), 4.19 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 10.01 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3; ¹³C NMR (75MHz, DMSO) δ 31.7, 50.7, 51.9, 52.5, 64.5, 101.1, 108.0, 116.5, 127.8,128.0, 128.3, 128.9, 137.3, 147.5 157.6; ES MS (M+1) 357.19; HRMS Calcd.For C₂₀H₂₄N₄O₂, 356.42. Found (M+1) 357.18.

Example 15

4-Azepan-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyridin-2-one ¹H NMR (300 MHz,DMSO) δ 1.61 (m, 4H), 1.80 (m, 4H), 3.20 (m, 4H), 4.17 (s, 2H), 5.16 (s,2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ88.9; ¹³C NMR (75 MHz, DMSO) δ 22.8, 26.4, 51.8, 53.4, 54.4, 107.6,117.2, 127.9, 128.0, 18.2, 128.9, 137.3, 147.2, 157.6; ES MS (M+1)313.18; HRMS Calcd. For C₁₉H₂₄N₂O₄, 312.41. Found (M+1) 313.19.

Example 16

4-Azocan-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyrdin-2-one ¹H NMR (300 MHz,DMSO) δ 1.59 (m, 10H), 3.18 (m, 2H), 3.38 (m, 2H), 4.17 (s, 2H), 5.16(s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ88.9; ¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 327.2; HRMS Calcd. ForC₂₀H₂₆N₂O₂, 326.43. Found (M+1) 327.20.

Example 17

1-Benzyl-4-(1,4′-bipiperidinyl-1′-ylmethyl)-3-hydroxy-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 1.43-1.98 (m, 10H), 2.21 (m, 2H), 3.01 (m, 4H),3.43 (m, 3H), 4.12 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34(m, 6H), 9.85 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.7; ¹³C NMR (75MHz, DMSO) δ 21.6, 22.9, 23.8, 49.6, -50.5, 51.8, 53.0, 59.5, 108.0,127.8, 128.0, 128.2, 128.9, 137.3, 147.5, 157.6; ES MS (M+1) 382.4; HRMSCalcd. For C₂₃H₃₁N₃O₂, 383.51. Found (M+1) 382.25.

Example 18

1-Benzyl-4-[(3,4-dihydro-2H-quinolin-1-yl)methyl]-3-hydroxy-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 3.13 (t, J=6.3 Hz, 2H), 3.52 (m, 2H), 4.28 (s,2H), 4.41 (s, 2H), 5.18 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.23-7.41 (m,10H), 10.15 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.9; ¹³C NMR (75MHz, DMSO) δ 25.4; 49.3, 51.8, 52.7, 52.9, 107.6, 11.6, 116.8, 126.9,127.0, 127.9, 128.0, 128.1, 128.2, 128.8, 128.9, 131.7, 137.3, 147.3,157.6; ES MS (M+1) 347.40; HRMS Calcd. For C₂₂H₂₂N₂O₂, 346.42. Found(M+1) 347.17.

Example 19

1-(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-ylmethyl)pyrrolidine-2-carboxylicacid methyl ester ¹H NMR (300 MHz, DMSO) δ 2.01 (m, 3H), 2.45 (m, 1H),3.26 (m, 1H), 3.53 (m, 1H), 3.69 (s, 3H), 4.30 (m, 3H), 5.17 (s, 2H),6.27 (d, 6.9 Hz, 1H), 7.35 (m, 6H), ¹⁹F NMR (252 MHz, DMSO) δ 88.3; 13CNMR (75 MHz, DMSO) δ; ES MS (M+1) 343.20; HRMS Calcd. For C₁₉H₂₂N₂O₄,342.39. Found (M+1).

Example 20

1-Benzyl-3-hydroxy-4-[(1-hydroxy-1-methylethyl)amino]methyl-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) d 1.27 (s, 6H), 3.49 (s, 2H), 3.95 (s, 2H), 5.17(s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H), 8.47 (broad s, 2H), 9.94(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.7; 13C NMR (75 MHz, DMSO) δ;ES MS(M+1) 303.19; HRMS Calcd. For C₁₇H₂₂N₂O₃, 302.37. Found (M+1)303.17.

Example 211-Benzyl-3-hydroxy-4-{[(pyridin-4-ylmethyl)amino]methyl}-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 2H), 4.32 (s, 2H), 5.16 (s, 2H), 6.34(d, J=7.2 Hz, 1H), 7.34 (m, 6H); 7.62 (d, J=5.7 Hz, 2H), 8.71 (d, J=4.5Hz, 2H); ¹⁹F NMR (252 MHz, DMSO) δ 88.0; ¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 322.17; HRMS Calcd. For C₁₉H₁₉N₃O₂, 321.37. Found (M+1) 322.15.

Example 22

1-Benzyl-3-hydroxy-4-[2-(methoxymethyl)pyrrolidin-1-ylmethyl]-1H-pyrdin-2-one¹H NMR (300 MHz, DMSO) δ 1.71 (m, 1H), 1.84 (m, 1H), 1.99 (m, 1H), 2.15(m, 1H), 3.19 (m, 1H), 3.30 (s, 3H), 3.41 (m, 1H), 3.62 (m, 2H), 3.77(m, 1H), 4.15 (m, 1H), 4.39 (m, 1H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz,1H), 7.34 (m, 6H); 9.60 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 329.2; HRMS Calcd. For C₁₉H₂₄N₂O₃,328.41. Found (M+1).

Example 231-Benzyl-4-{[(furan-2-ylmethyl)amino]methyl}-3-hydroxy-1H-pyrdin-2-one

¹H NMR (300 MHz, DMSO) δ 4.00 (s, 2H), 4.28 (s, 2H), 5.16 (s, 2H), 6.27(d, J=6.9 Hz, 1H), 6.54 (m, 1H), 6.65 (m, 1H), 7.34 (m, 6H), 7.80 (m,1H), 9.27 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3; ¹³C NMR (75MHz, DMSO) δ; ES MS (M+1) 323.15; HRMS Calcd. For C₁₈H₁₈N₂O₃, 310.35.Found (M+1).

Example 241-Benzyl-3-hydroxy-4-[(2-methylsulfanylethylamino)methyl]-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 2.10 (s, 3H), 2.74 (t, J=6.9 Hz, 2H), 3.16 (t,J=8.1 Hz, 2H), 4.05 (s, 2H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34(m, 6H), 19F NMR (252 MHz, DMSO) δ 89.0; ES MS (M+1) 305.14, HRMS Calcd.For C₁₆H₂₀N₂O₂S, 304.41. Found (M+1).

Example 25

1-Benzyl-3-hydroxy-4-[2-(pyrdin-2-yl)pyrrolidin-1-ylmethyl]-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 2.12 (m, 4H), 3.39 (m, 1H), 3.63 (m, 1H), 4.07(m, 2H), 4.60 (m, 1H), 5.10 (m, 2H), 6.15 (d, J=6.9 Hz, 1H), 7.33 (m,6H), 7.44 (m, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.74(s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.0; ES MS (M+1) 362.22; HRMS Calcd.For C₂₂H₂₃N₃O₂, 361.44. Found (M+1).

Example 26

1-Benzyl-3-hydroxy-4-[(4-methoxybenzylamino)methyl]-1H-pyridin-2-one ¹HNMR (300 Mhz, DMSO) δ 3.70 (s, 3H), 3.98 (s, 2H), 4.13 (s, 2H), 5.16 (s,2H), 6.28 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 4H), 7.34 (m, 6H); 9.07(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 89.0; ES MS (M+1) 351.10; HRMSCalcd. For C₂₁H₂₂N₂O₃, 350.41. Found (M+1) 351.17.

Example 274-((1-(4-methoxyphenyl)ethylamino)methyl)-1-benzyl-3-hydroxypyridin-2(1H)-one

¹H NMR (300 MHz, DMSO) δ 1.59 (d, J=7.2 Hz, 3H), 3.71-3.93 (m, 2H), 4.45(m, 1H), 5.15 (s, 2H), 6.28 (d, J=7.5 Hz, 1H), 7.34 (m, 1H); ¹⁹FNMR (252MHz, DMSO) δ 88.9; ¹³C NMR (75 MHz, DMSO) δ 19.6, 42.5, 51.7, 58.0,106.8, 119.3, 128.0, 128.1, 128.2, 128.9, 129.3, 129.4, 137.3, 145.9,158.3; ES MS (M+1) 335.13; HRMS Calcd. For C₂₁H₂₂N₂O₂, 334.41. Found(M+1) 335.17.

Example 281-Benzyl-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]-3-hydroxy-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 3.18 (m, 2H), 3.48 (m, 4H), 4.19 (s, 2H), 4.46(m, 2H), 5.16 (s, 2H), 6.62 (d, J=7.2 Hz, 1H), 7.35 (m, 6H), 7.48 (m,1H), 7.68 (m, 1H), 11.5 (broad s, 1H); ¹³C NMR (75 MHz, DMSO) δ 42.1,50.3, 51.9, 52.5, 108.2, 116.2; 118.0, 128.0, 128.2, 128.9, 129.8,137.3, 147.4, 157.6, 158.8; ES MS (M+1) 476.09. HRMS Calcd. ForC₂₁H₂₂ClN₅N₃O₂, 411.88. Found (M+1) 412.76.

Example 29

1-Benzyl-3-hydroxy-4-{[3-(1H-imidazol-1-yl)ethylamino]methyl}-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 2.19 (m, 2H), 2.97 (m, 2H), 4.02 (s, 2H), 4.30(t, J=6.6 Hz, 2H); 5.17 (s, 2H), 6.30 (d, J=6.9 Hz, 1H), 7.36 (m, 6H),7.26 (s, 1H), 7.76 (s, 1H), 9.03 (s, 1H), 9.11 (s, 1H); ¹⁹F NMR (252MHz, DMSO) δ 88.5; 13C NMR (75 MHz, DMSO) δ 26.5, 44.0, 46.0, 51.8,106.8, 118.7, 120.5, 122.2, 127.9, 128.2, 128.9, 135.8, 137.4, 146.0,158.2; ES MS (M+1) 339.05; HRMS Calcd. For C₁₉H₂₂N₄O₂, 338.44. Found(M+1) 339.18.

Example 30

1-Benzyl-4-(cycloheptylamino)methyl-3-hydroxy-1H-pyrdin-2-one ¹H NMR(300 MHz, DMSO) δ 1.55 (m, 10H), 2.03 (m, 2H), 3.18 (s, 1H), 3.99 (m,2H), 5.17 (s, 2H), 6.32 (d, J=6.9 Hz, 1H), 7.35 (m, 6H), 8.65 (broad s,2H), 9.98 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) d 88.6; ¹³C NMR (75MHz, DMSO) δ 23.0, 27.2, 30.4, 41.6, 51.7, 58.9, 107.0, 111.7, 127.9,128.0, 128.2, 128.8, 137.4, 146.0, 157.5; ES MS(M+1) 327.13; HRMS Calcd.For C₂₀H₂₆N₂O₂, 326.43. Found (M+1) 327.20.

Example 311-Benzyl-3-hydroxy-4-[(4-methylcyclohexylamino)methyl]-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 0.93 (d, J=6.9 Hz, 3H), 1.38 (m, 4H), 1.74 (m,4H), 2.05 (m, 1H), 3.10 (m, 1H), 4.01 (s, 2H), 5.17 (s, 2H), 6.31 (m,1H), 7.34 (m, 6H), 8.05 (broad s, 2H), 9.98 (broad s, 1H); ¹⁹F NMR (252MHz, DMSO) δ 88.9; ¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 327.14; HRMSCalcd. For C₂₀H₂₆N₂O₂, 326.43; Found (M+1) 372.20.

Example 321-Benzyl-4-[(1-benzylpiperidin-4-ylamino)methyl]-3-hydroxy-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 1.77 (m, 2H), 2.31 (m, 2H), 2.98 (m, 2H), 3.30(m, 3H), 3.46 (m, 2H), 4.03 (s, 2H), 0.29 (s, 2H), 5.16 (s, 2H), 6.30(d, J=7.5 Hz, 1H), 7.34 (m, 6H), 7.49 (s, 5H), 9.12 (broad s, 1H), 10.05(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.8; ¹³C NMR (75 MHz, DMSO) δ27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.6, 106.9, 118.5, 128.0, 128.1,128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.4; ES MS (M+1)404.56; HRMS Calcd. For C₂₅H₂₈N₃O₂, 403.52. Found (M+1) 404.23.

Example 33

3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methylamino]azepan-2-one¹H NMR (300 MHz, DMSO) δ 1.25 (m, 1H), 1.59 (m, 2H), 1.74 (m, 1H), 1.92(m, 1H), 2.10 (m, 1H), 3.18 (m, 3H), 4.03 (s, 2H), 4.2 (m, 1H), 5.17 (s,2H), 6.33 (d, J=7.5 Hz, 1H), 7.34 (m, 6H), 8.31 (t, J=5.4 Hz, 1H), 9.07(broad s, 2H), 9.90 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.4; ¹³CNMR (75 MHz, DMSO) δ 27.0, 27.2, 28.4, 43.4, 51.7, 59.3, 107.1, 118.9,127.8, 127.9, 128.1, 128.9, 137.4, 146.0, 157.5, 166.3; ES MS (M+1)342.01; HRMS Calcd. For C₁₉H₂₃N₃O₃, 341.40. Found (M+1) 342.18.

Example 341-Benzyl-4-[(1-benzylpyrrolidin-3-ylamino)methyl]-3-hydroxy-1H-pyridin-2-one

¹H NMR (300 MHz, DMSO) δ 2.22 (m, 2H), 2.42 (m, 1H), 3.39 (m, 3H), 3.68(m, 1H), 4.06 (s, 2H), 4.39 (s, 2H), 5.17 (s, 2H), 6.33 (d, J=7.5 Hz,1H), 7.30-7.52 (m, 11H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5; 13C NMR (75MHz, DMSO) δ 27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.5, 106.9, 118.5,128.0, 128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.5; ES MS(M+1) 390.14; HRMS Calcd. For C₂₄H₂₇N₃O₂, 389.49. Found (M+1) 390.21.

Example 35

3-Hydroxy-1-(3-methoxybenzyl)-4-pyrrolidin-1-ylmethyl-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 1.89 (m, 2H), 1.99 (m, 2H), 3.07 (m, 2H), 3.41(m, 2H), 3.74 (s, 3H), 4.17 (m, 2H), 5.17 (s, 2H), 6.51 (d, J=7.2 Hz,1H), 6.90 (m, 3H), 7.27 (t, J=7.5 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 9.98(broad s, 1H), 10.72 (broad s, 1H); ¹³C NMR (75 MHz, DMSO) δ 23.0; 50.3,51.7; 53.2; 55.4, 107.6, 113.2, 114.2, 118.2, 120.3, 127.8, 130.0, 18.8,146.4, 157.6, 159.6; ES MS (M+1) 315.82; HRMS Calcd. For C₁₈H₂₂N₂O₃,314.38. Found (M+1) 315.17.

Example 36

3-Hydroxy-1-pyridin-4-ylmethyl-4-pyrrolidin-1-ylmethyl-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 1.81 (m, 4H), 3.05 (t, J=6.0 Hz, 4H), 4.23 (s,2H), 5.48 (s, 2H), 6.76 (d, J=7.2 Hz, 1H), 7.49 (d, J=6.6 Hz, 1H), 7.83(d, J=6.0 Hz, H), 8.89 (d, J=6.0 Hz, 2H), 9.53 (broad s, 2H), 11.5(broad s, 1H), ¹³C NMR (75 MHz, DMSO) δ 22.7, 24.1, 44.5, 48.8, 50.1,53.0, 108.2, 119.1, 125.3, 127.7, 42.1, 146.5, 156.7, 158.3; ES MS (M+1)286.99; HRMS Calcd. For C₁₆H₁₉N₃O₂, 285.34. Found (M+1) 286.15.

Example 37

1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-1H-pyridin-2-one¹H NMR (300 MHz, DMSO) δ 2.95 (m, 2H), 3.30 (m, 2H), 3.48 (m, 4H), 3.80(s, 3H), 4.25 (s, 2H), 5.18 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 6.93 (m,2H), 7.01 (m, 2H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5; 13C NMR(75 MHz, DMSO) δ 47.2, 51.8, 53.0, 55.3, 108.1, 112.2, 114.8, 116.2,118.6, 121.2, 123.8, 127.8, 128.0, 128.9, 137.3, 139.6, 147.5, 152.2,157.6; ES MS (M+1) 405.82; HRMS Calcd. For C₂₄H₂₇N₃O₃, 405.49. Found(M+1) 406.21.

Example 38

1-Benzyl-3-hydroxy-4-[(1-phenylethyl-R-amino)methyl]-1H-pyridin-2-one ¹HNMR (300 MHz, DMSO) δ 1.58 (d, J=6.9 Hz, 3H), 3.74 (m, 2H), 4.44 (m,1H), 5.14 (s, 2H), 6.23 (d, J=7.2 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR-(252MHz, DMSO) δ 89.4; ¹³C NMR (75 MHz, DMSO) δ 19.6, 42.6, 51.7, 58.0,106.9, 18.7, 128.0, 128.1, 128.8, 129.3, 129.4, 137.2, 137.4, 145.9,157.5; ES MS (M+1) 335.13; Anal. Calcd. For C₂₁H₂₂N₂O₂, 334.41. Found(M+1) 335.31.

Except as otherwise noted, all amounts including quantities,percentages, portions, and proportions, are understood to be modified bythe word “about”, and amounts are not intended to indicate significantdigits.

Except as otherwise noted, the articles “a”, “an”, and “the” mean “oneor more”.

Except as otherwise noted, the articles “a”, “an”, and “the” mean “oneor more”.

To the extent that any meaning or definition of a term in this writtendocument conflicts with any meaning or definition of the term in adocument incorporated by reference, the meaning or definition assignedto the term in this written document shall govern.

All documents cited in the Detailed Description of the Invention are, inrelevant part, incorporated herein by reference; the citation of anydocument is not to be construed as an admission that it is prior artwith respect to the present invention.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

1. A compound of formula (I):

wherein: a) each R₁ is independently chosen from hydrogen, halo, cyano,hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido,aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,and cycloalkyl; b) each R₂ is independently chosen from hydrogen, halo,cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido,phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl,alkoxy, aryl, and cycloalkyl; c) R₃ and R₄, together with the nitrogenatom to which they are bonded, join to form a piperidin-1-yl unit,optionally substituted with one or more halo, cyano, hydroxy, carboxy,keto, thioketo, amino, acylamino, acyl, amido, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl,wherein the aryl ring can be substituted with from 1 to 4 halo, cyano,hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido,aryloxy, alkyl, alkenyl, alkynyl, and combinations thereof; and d) R₅and R₆ are each independently chosen from of hydrogen, halo, cyano,hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido,aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, aryl,and cycloalkyl; or optical isomers, diastereomers and enantiomers of theformula above, or a pharmaceutically-acceptable salt.
 2. The compound ofclaim 1, wherein each R₁ is hydrogen.
 3. The compound of claim 1,wherein R₁ is one or more alkoxy.
 4. The compound of claim 1, wherein R₁is a heteroalkyl.
 5. The compound of claim 1, wherein R₁ is an aryl. 6.The compound of claim 1, wherein R₁ one or more methyl.
 7. The compoundof claim 1, wherein R₁, R₂, R₅ and R₆ are hydrogen.
 8. The compound ofclaim 1, wherein R₂ is hydrogen.
 9. The compound of claim 1, wherein R₅and R₆ are hydrogen.
 10. The compound of claim 1, chosen from:1-Benzyl-3-Hydroxy-4-piperidin-1-ylmethyl-1H-pyridin-2-one; and1-Benzyl-4-(4-benzylpiperidin-1-ylmethyl)-3-hydroxy-1H-pyridin-2-one.11. A method of treating a microbial infection comprising administeringa safe and effective amount of a compound according to claim 1, to asubject in need thereof.
 12. A method of treating a microbial infectioncomprising administering a safe and effective amount of a compoundaccording to claim 10, to a subject in need thereof.
 13. Apharmaceutical composition comprising: a) a safe and effective amount ofa compound according to claim 1; and b) a pharmaceutically-acceptableexcipient.
 14. A pharmaceutical composition comprising: a) a safe andeffective amount of a compound according to claim 10; and b) apharmaceutically-acceptable excipient.